Process for the Preparation of (3E, 7E)-Homofarnesol

ABSTRACT

The present invention relates to new types of processes for the improved preparation of homofarnesol, in particular of (3E,7E)-homofarnesol and homofarnesol preparations with an increased content of (3E,7E)-homofarnesol (also referred to as all E-homofarnesol).

The present invention relates to new types of processes for the improved preparation of homofarnesol, in particular of (3E,7E)-homofarnesol and homofarnesol preparations with an increased content of (3E,7E)-homofarnesol (also referred to as all E-homofarnesol).

BACKGROUND OF THE INVENTION

Ambrox® is the trade name of the enantiomerically pure compound (−)-ambrox (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan), a sought-after fragrance. Naturally occurring (−)-ambrox is the olfactory most important ingredient of ambergris, a digestion product of sperm whales.

The different diastereomers of (−)-ambrox have a similar scent, but sometimes differ in their odor thresholds (G. Ohloff, W. Giersch, W. Pickenhagen, A. Furrer, B. Frei, Helv. Chim. Acta 68 (1985) 2022. G. Fráter, J. A. Bajgrowicz, P. Kraft, Tetrahedron 54 (1998) 7633). The odor threshold of 3a-epi-(−)-ambrox is higher than that of (−)-ambrox by a factor of 100. By contrast, 9b-epi-(−)-ambrox has half as high an odor threshold as (−)-ambrox for virtually the same odor quality. (+)-Ambrox is eight times weaker than the natural enantiomer. The racemate has an odor threshold of 0.5 ppb and barely differs from that of (−)-Ambrox® in its tonalities. (B. Schäfer Chemie in unserer Zeit 2011, 45, 374).

Homofarnesol is an important intermediate of synthesis processes for preparing Ambrox® (R. L. Snowden, Chemistry & Biodiversity 2008, 5, 958. J. and D. Leffingwell Specialty Chemical Magazine 2011, 30).

In particular, the cyclization of all E-homofarnesol of the formula Ia

produces diastereomerically pure or enantiomerically pure ambrox (Super acids: P. F. Vlad et al. Khimiya Geterotsiklicheskikh Soedinenii, Engl. Transl. 1991, 746; R. L. Snowden, Chemistry & Biodiversity 2008, 5, 958. Lewis acid-Brönsted acid: K. Ishihara et al. J. Am. Chem. Soc. 2002, 124, 3647. Mechanistic investigations: R. L. Snowden et al. J. Org. Chem. 1992, 57, 955.).

The literature describes various processes for preparing all E-homofarnesol:

(1) stereoisomerically pure (3E,7E)-homofarnesol can be prepared from (E,E)-farnesol via (E,E)-farnesal, C1 extension according to Wittig with methylenetriphenyl-phosphorane and subsequent terminal hydroboration of the conjugated diene in accordance with a synthesis described in the literature (D. S. Dodd et al. J. Org. Chem. 1992, 57, 2794).

However, this synthesis is not a technically-economically sensible route to (E,E)-homofarnesol. A technical process for preparing isomerically pure farnesol is not given.

(2) An alternative known in the literature for the synthesis of (3E,7E)-homofarnesol consists in the following procedure (A. F. Barrero et al. J. Org. Chem. 1996, 61, 2215.): a) distillative separation of (E/Z)-nerolidol, b) reaction of (E)-nerolidol with dimethylformamide dimethylacetal (DMFDMA) in a Büchi rearrangement to give the corresponding (3E/Z, 7E)-C₁₆-amides, c) flash-chromatographic separation of the stereoisomeric amides and d) reduction of the (3E,7E)-amide to the corresponding (3E,7E)-homofarnesol with lithium triethylborohydride. Disadvantages of this route are the moderate yields and the required flash chromatography for separating the stereoisomers.

(3) A patent application from Henkel (WO 92/06063, Henkel Research Corporation) describes the carbonylation of (E)-nerolidol with the addition of catalytic amounts of the relatively expensive reagent palladium (II) chloride. Furthermore, the reaction takes place disadvantageously for the implementation at high CO pressures of ca. 70 bar.

(4) A further literature source (P. Kocienski et al. J. Org. Chem. 1989, 54, 1215.) describes the synthesis of homofarnesol from dihydrofuran. Each cycle requires the alkylation of 5-lithio-2,3-dihydrofuran with a homoallylic iodide followed by Ni(O)-catalyzed coupling with methylmagnesium bromide. The resulting homogeraniol can be converted to the corresponding iodide and the cycle is repeated. The synthesis is E-selective and produces the homofarnesol over 5 stages in an overall yield of ca. 70%.

The first three processes described above never arrive directly at the oxidation state of homofarnesol. Furthermore, expensive hydride reagents are required for reducing the homofarnesylic acid. Process (4) is economically unattractive on account of the reagents required.

The objective of the invention is therefore the provision of an improved process for the preparation of homofarnesol, in particular (3E,7E)-homofarnesol, and structurally analogous compounds.

SUMMARY OF THE INVENTION

This object was achieved in general by the process according to the invention as per claim 1 and in particular by a specific embodiment of this process for the preparation of (3E,7E)-homofarnesol.

The synthesis strategy is essentially based on the coupling of a C₁₋₃- and C₃-building block in a Wittig reaction. The C₃ building block is the cyclopropylphosphonium salt known in the literature (A. Brandi et al. Chem. Rev. 1998, 589 and literature cited therein). The C₁₃ building block geranyl acetone is available industrially and cost-effectively as intermediate from the citral value-addition chain. The desired (E)-isomer is obtainable by distillation. This coupling strategy can be transferred to shorter- or longer-chain homologs of the C₁₃ building block geranyl acetone.

DETAILED DESCRIPTION OF THE INVENTION a) General Definitions

Unless statements are made to the contrary, the following general meanings are applicable:

“Ambrox” comprises in particular (−)-ambrox of the formula

in stereoisomerically pure form or optionally in a mixture with at least one of the following diastereomers:

“Enantiomerically pure” means that, besides the specifically named enantiomer, no other enantiomeric form of a chemical compound having at least one center of a symmetry can be detected analytically.

“Hydrocarbyl” is to be interpreted in the wide sense and comprises straight-chain or mono- or polybranched hydrocarbon radicals having 1 to 50 carbon atoms which can optionally additionally comprise heteroatoms, such as e.g. O, N, NH, S, in their chain. In particular, hydrocarbyl stands for straight-chain, and especially mono- or polybranched hydrocarbon radicals of the above chain length but without heteroatom. Hydrocarbyl comprises, for example, the alkyl or alkenyl radicals defined below and substituted analogs thereof, in particular straight-chain or branched C₁-C₂₀-, C₁-C₁₀- or C₁-C₆-alkyl radicals, or straight-chain or branched, monounsaturated or polyunsaturated, like 1-, 2-, 3-, 4- or 5-fold unsaturated alkenyl radicals with conjugated or in particular non-conjugated double bonds.

“Alkyl” stands in particular for saturated, straight-chain or branched hydrocarbon radicals having 1 to 4, 1 to 6, 1 to 8, 1 to 10, 1 to 14 or 1 to 20, carbon atoms, such as e.g. methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-di-methylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl; and also n-heptyl, n-octyl, n-nonyl and n-decyl, n-dodecyl, n-tetradecyl, n-hexadecyl, and also the mono- or polybranched analogs thereof.

“Alkoxy” stands for the Oalkyl analogs of the above alkyl radicals, such as e.g. methoxy, ethoxy, n-propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy; and also e.g. pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy or 1-ethyl-2-methylpropoxy.

“Alkenyl” stands in particular for the unsaturated, straight-chain or branched analogs of the above alkyl radicals and have in particular 2 to 4, 2 to 6, 2 to 8, 2 to 10, 2 to 14 or 2 to 20, carbon atoms. In particular, these can be monounsaturated or polyunsaturated, such as e.g. diunsaturated, triunsaturated, tetraunsaturated or pentaunsaturated. The double bonds here are non-cumulated double bonds. In particular, the double bonds are conjugated or in particular non-conjugated. For example, a suitable alkenyl radical optionally comprises repetitive isoprene-like structural elements

where n can be a whole-numbered value from 1 to 8, such as e.g. 1, 2, 3 or 4.

“Acyl” (as such or as part of “Oacyl” radicals) stands in particular for radicals derived from straight-chain or branched, optionally mono- or polyunsaturated, optionally substituted C₁-C₂₄-, such as e.g. C₁-C₆- or C₁-C₄-monocarboxylic acids. For example, acyl radicals which can be used are derived from the following carboxylic acids: saturated acids, such as formic acid, acetic acid, propionic acid and n- and i-butyric acid, n- and isovaleric acid, caproic acid, oenanthic acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, margaric acid, stearic acid, nonadecanoic acid, arachic acid, behenic acid, lignoceric acid, cerotic acid and melissic acid; monounsaturated acids, such as acrylic acid, crotonic acid, palmitoleic acid, oleic acid and erucic acid; and diunsaturated acids, such as sorbic acid and linolic acid. If double bonds are present in the fatty acids, then these can be present either in the cis form or in the trans form.

“Aryl” stands in particular for mono- or polynuclear, preferably mono- or dinuclear, in particular mononuclear, optionally substituted aromatic radicals having 6 to 20, such as e.g. 6 to 10, ring carbon atoms, such as e.g. phenyl, biphenyl, naphthyl, such as 1- or 2-naphthyl, tetrahydronaphthyl, fluorenyl, indenyl and phenanthrenyl. These aryl radicals can optionally carry 1, 2, 3, 4, 5 or 6 identical or different substituents, for example selected from halogen, alkyl, in particular having 1 to 4 carbon atoms, alkenyl, in particular having 2 to 4 carbon atoms, OH, alkoxy, in particular having 1 to 4 carbon atoms, acyl, in particular having 1 to 4 carbon atoms, NH₂ or NO₂.

“Halogen” stands for F, Cl, Br or I.

b) Specific Embodiments

The present invention relates in particular to the following embodiments:

-   1. Process for the preparation of compounds of the general formula

-   -   in which     -   R₁ is a straight-chain or branched, optionally monounsaturated         or poly- (such as e.g. mono- or di-) unsaturated hydrocarbyl         radical, e.g. C₁-C₂₀, C₁-C₁₁ or C₁-C₆ hydrocarbyl, like in         particular a straight-chain or branched C₁-C₂₀, C₁-C₁₁ or C₁-C₆         alkyl radical or a straight-chain or branched C₂-C₂₀-, C₂-C₁₀-         or C₂-C₆-alkenyl radical with one or more conjugated or         non-conjugated double bonds, or e.g. a radical of the isoprene         type of the formula

-   -   in which n is 1, 2, 3, 4 or 5;     -   and R₂ is H or C₁-C₆-alkyl, in particular methyl or ethyl, where     -   a) a carbonyl compound of the formula II

-   -   in which R₁ and R₂ have the meanings given above,     -   is reacted by means of Wittig olefination to give a cyclopropane         of the general formula (III)

-   -   in which R₁ and R₂ have the meanings given above,     -   b) the cyclopropane of the formula III is reacted, with ring         opening, to give a compound of the formula IV

-   -   in which R₁ and R₂ have the meanings given above, and X is         halogen, such as e.g. Cl or Br, or O—R″, in which R′ is H, acyl,         such as C₁-C₄-acyl, in particular acetyl, Tf-acetyl or SC₂—R″,         in which R″ is alkyl, in particular C₁-C₄-alkyl or optionally         substituted aryl, in particular optionally substituted phenyl;         and     -   c) the compound of the general formula IV is converted to the         compound of the general formula I.

-   2. Process according to embodiment 1, where a cyclopropylphosphonium     salt is used for the Wittig olefination according to stage a).

-   3. Process according to embodiment 2, in which the     cyclopropylphosphonium salt is a triphenylphosphonium compound of     the formula V

-   -   in which Z⁻ is the anion of a strong acid, such as in particular         a halide, such as e.g. fluoride, chloride or bromide, preferably         bromide.

-   4. Process according to embodiment 3, where the compound of the     formula V is prepared by a) reacting bromobutyrolactone with     triphenylphosphine and then thermally decarboxylating the reaction     product, or b) reacting 1,3-dibromopropane with triphenylphosphine,     in particular in the presence of a base, such as in particular a     base without nucleophilic properties (such as e.g. PhLi, NaH, K     tert-butylate) and then cyclizing the reaction product.

-   5. Process according to one of the preceding embodiments, in which     the ring opening of stage b) takes place in the presence of a Lewis     acid (such as e.g. AlCl₃, BF₃, SiCl₄, PF₅, Sn(OTf)₂, Cu(OTf)₂) or     Brönstedt acid/protonic acid (such as, e.g. formic acid, acetic     acid, propionic acid, sulfuric acid, pivalic acid, isobutyric acid,     alkyl- and arylsulfonic acids, e.g. methanesulfonic acid or     para-toluenesulfonic acid) and of a nucleophile (such as e.g. OH″,     formate, acetate, propionate, pivalate, isobutyrate, alkyl- and     arylsulfonate, e.g. methanesulfonate or para-toluenesulfonate,     chloride, bromide), where Tf is trifluoromethanesulfonyl.

-   6. Process according to embodiment 5, where the ring opening takes     place essentially stereoselectively, in particular E-selectively     (with respect to R₁).

-   -   E-selectivity is present here particularly when, after ring         opening, the E form is formed in quantitative (molar) excess         (i.e. E:Z>1, such as e.g. >1.01, such as e.g. >1.5 or >2, such         as e.g. in the range from 1.5 to 100, 2 to 50 or 2.2 to 10; or E         is formed quantitatively, i.e. Z form cannot be detected         analytically.

-   7. Process according to one of the preceding embodiments, where, in     stage c), the compound of the general formula IV is converted to a     compound of the general formula I by, when X is Oacyl, such as e.g.     Oacetyl, carrying out an ester cleavage, or when X is halogen, such     as e.g. Cl or Br, converting the halide into an ester, as e.g. with     a salt of formic acid (e.g. sodium formate) to the corresponding     formic acid ester and then cleaving this ester.

-   8. Process according to one of the preceding embodiments, in which a     product comprising a (3E,7E)-homofarnesol of the formula Ia

-   -   is obtained.

-   9. Process according to embodiment 8, where, in stage a), E-geranyl     acetone of the formula IIa

-   -   is reacted with cyclopropylphosphonium halide such that the         cyclopropane of the formula IIIa

-   -   is obtained.

-   10. Compounds of the formula III, in particular of the formula IIIa.

-   11. Process for the preparation of enantiomerically pure ambrox or     of a stereoisomer mixture of ambrox, where (3E,7E)-homofarnesol is     prepared according to a process as per one of the proceeding     embodiments 1 to 9, and the homofarnesol formed in this way is     reacted chemically or enzymatically in a manner known per se to give     enantiomerically pure or racemic ambrox or any desired stereoisomer     mixtures thereof.

c) Detailed Description of the Process according to the Invention

The principle of the process according to the invention is illustrated in more detail by reference to a preferred embodiment for the preparation of all E-homofarnesol, without being limited to this specific reaction. Specific configurations can therefore be transferred to other starting compounds used.

The C₁₆ building block (E)-C₁₆-cyclopropane can be obtained by Wittig olefination of (E)-geranyl acetone with the cyclopropyltriphenylphosphonium salt as follows:

The C₃ salt can be prepared in accordance with procedures in the literature from α-bromobutyrolactone in two stages via a C₄ salt as intermediate (S. Fliszár et al. Helv. Chim. Acta 1963, 46, 1580. H. J. Bestmann et al. Tetrahedron Lett. 1966, 3591. E. E. Schweizer et al. J. Chem. Soc., Chem. Comm. 1966, 666. H. J. Bestmann et al. Angewandte Chemie 1965, 77, 1011.):

An alternative to the C₃ salt synthesis starting from 1,3-dibromopropane is likewise known in the literature (K. Sisido et al. Tetrahedron Lett. 1966, 3267. A. Maercker et al. Tetrahedron 1994, 50, 2439. K. Utimoto et al. Tetrahedron 1973, 29, 1169., E. E. Schweizer et al. J. Org. Chem. 1968, 33, 336.):

Classic Wittig olefinations with cyclopropyltriphenylphosphonium bromide have only been described little in the literature (A. Brandi et al. Chem. Rev. 1998, 589 and literature cited therein. M. Giersig et al. Chem. Ber. 1988, 525.). The yields for these. Wittig reactions with various ketones (e.g. cyclohexanone, benzophenone) are between 43% and 80%. To avoid secondary reactions, bases without nucleophilic properties (PhLi, NaH, K tert-butylate) are used, as in the present case the relatively cost-effective base K tert-butylate or NaH. In general, in the Wittig reactions, the yields for trisubstituted olefins are generally low, and for tetrasubstituted olefins are even worse (H. G. Ernst, Carotenoids, Volume 2, Synthesis, P. 80f.).

Surprisingly, it has been established according to the invention that the Wittig olefination of cyclopropyltriphenylphosphonium bromide with an aliphatic ketone such as (E)-geranyl acetone using potassium tert-butylate to give (E)-C₁₆-cyclopropane proceeds in yields>90% (see example 1). The Wittig reaction can take place using 2 eq of NaH also starting from TPP-bromopropane salt and in situ cyclization to the cyclopropylphosphonium salt in a very good yield of >90% (see example 2).

(E)-C₁₆-cyclopropane, which is hitherto unknown in the literature, can be opened in the presence of an acid, e.g. a Lewis acid such as AlCl₃ or BF₃*Et₂O and a nucleophile in a regioselective and stereoselective way to give homofarnesyl derivates.

The ring opening of alkylidene cyclopropane derivatives has been described in the literature (H. Pellissier Tetrahedron 2010, 66, 8341 and literature cited therein), although, as happened in our case, no side chains with double bonds were observed (see examples 3 and 4).

Homofarnesyl chloride can then be converted to homofarnesol by means of classic acetate substitution and hydrolysis. Alternatively, homofarnesoyl can be synthesized in accordance with the literature (H. A. Zahalka et al. Synthesis 1986, 763.) starting from homofarnesyl chloride via the formate and subsequent hydrolysis (see example 5).

3E,7E- and 3Z/7E-homofarnesol and the corresponding 3Z-isomers can be separated by distillation such that pure 3E,7E-homofarnesol is obtained.

The homofarnesol obtained in this way can then be cyclized in a further step to give ambrox (see example 6).

This cyclization can take place here in a manner known per se or as described in the working examples below. Both enzymatic and chemical cyclizations are contemplated for this purpose.

Thus, for example, the enzymatic cyclization by means of squalene hopene cyclase is known from WO 2010/139719, to which reference is hereby expressly made.

Chemical cyclization reactions using a super acid (fluorosulfonic acid in 2-nitropropane) are known e.g. from P. F. Vlad et al. Khimiya Geterotsiklicheskikh Soedinenii, Engl. Transl. 1991, 746. Further processes comprise a cyclization comprising the enantioselective polyene cyclization of homofarnesyl triethylsilyl ether in the presence of O-(o-fluorobenzyl)binol and SnCl₄, as described by Yamamoto (H. Yamamoto et al. J. Am. Chem. Soc. 2002, 3647.)

Experimental Section A) Material and Methods HPLC Analysis: Method 1) Instrument Settings and Chromatographic Conditions:

Instrument: Agilent Series 1100

Column: Zorbax Eclipse XDB-C18 1.8 μm 50*4.6 mm combined with a Zorbax

Extend C18 1.8 μm 50*4.6 mm from Agilent®

Eluent: —A: Water with 0.1% by volume H₃PO₄

-   -   —B: Acetonitrile with 0.1% by volume H₃PO₄

Time in min % B Flow 0.0 70 1 10.0 80 1 13.0 100 1 17.0 100 1 17.1 70 1

Detector: UV detector λ=197 nm, BW=4 nm

Flow rate: 1 ml/min

Injection: 1 μL

Temperature: 50° C.

Run time: 20 min

Pressure: ca. 160 bar

Method 2) Instrument Settings and Chromatographic Conditions:

Instrument: Agilent Series 1100

Column: Chiralpak AD-RH 5 μm 150*4.6 mm from Daicel®

Eluent: —A: Water with 0.1% by volume H₃PO₄

-   -   —B: Acetonitrile with 0.1% by volume H₃PO₄

Time in min % B Flow 0.0 30 1.2 25.0 70 1.2 30.0 100 1.2 40.0 100 1.2 40.1 30 1.2

Detector: UV-Detector λ=205 nm, BW=5 nm

Flow rate: 1.2 ml/min

Injection: 5 μL

Temperature: 40° C.

Run time: 45 min

Pressure: ca. 70 bar

B) Preparation Examples Example 1 Wittig Reaction Starting from the Cyclopropylphosphonium Salt with Potassium Tert-Butylate

Feed Materials:

640 ml (7890.58 mmol) I Tetrahydrofuran 24.7 eq   598.96 g M = 72.11 g/mol 122.6 g (320 mmol) II Cyclo- 1 eq propylphosphonium salt M = 383.27 g/mol 35.91 g (320 mmol) III Potassium tert-butylate 1 eq M = 112.21 g/mol 48.6 g (288 mmol) IV E-Geranyl acetone 0.9 eq   M = 194.32 g/mol The reactor is flushed with nitrogen. 500 ml of THF (I) are introduced as initial charge and cooled to 0° C. Cyclopropylphosphonium salt (II) comminuted in the mortar is added rinsed with the remaining amount (140 ml) of THF (I) and stirred at 0° C. for 8 min. Under an N₂ atmosphere, potassium tert-butylate (III) is added, during which the internal temperature increases to 5° C. The suspension becomes immediately red-orange, and is then stirred at ca. 0° C. for 2 hours.

Geranyl acetone (IV) is added dropwise over the course of ca. 10 min (slight exothermyl), then stirring is carried out for 15 min at an oil temperature of −2° C. The reaction mixture is then heated with delta 1° C. (oil temperature to internal temperature). When an internal temperature of 35° C. is reached, stirring is continued overnight at an oil temperature of 35° C. After a total stirring time of 24 h (conversion check via TLC: n-heptane/EE=10:1), the mixture is worked up. At an internal temperature of 35° C., 1000 ml of n-heptane are added to the reaction suspension, and distillate is drawn off by regulating the vacuum such that the internal temperature does not exceed 35° C.; heating with delta 15° C. relative to the internal temperature. At a pressure of 155 mbar, the oil temperature is reduced to 35° C., then aerated with N₂. Distillate and cold trap are emptied. (Fraction 1: 494 g, of which 259 g THF according to GC A %). The apparatus is evacuated to 150 mbar. By regulating the vacuum, distillate is drawn off such that the internal temperature does not exceed 35° C.; heating with delta 15° C. relative to the internal temperature. At a pressure of 95 mbar, the oil temperature is reduced to 20° C., then aerated with N₂. Distillate and cold trap are emptied (fraction 2: 292 g, of which 63 g THF according to GC A %). In total, ca. 320 g of THF (according to GC A %, although n-heptane is over evaluated) of 569 g was distilled off.

530 g of water are stirred into the reactor contents (suspension, 20° C.), phase separation after ca. 5 min. The lower phase 1 (LP1, 395 g, pale brown) is discarded. The upper phase 1 with TPPO detritus is stirred with 500 ml of water for 5 min, phase separation after 5 min. The lower phase 2 (LP2, 559 g, pale brown) is discarded. The upper phase 2 with TPPO detritus is stirred with 500 ml water/methanol (1:1 parts by volume, 455 g) for 5 min; the stirrer is switched off. The TPPO is not completely dissolved in the water/MeOH. Phase separation takes place after 5 min. Lower phase 3 (LP3, 545 g, cloudy phase). The upper phase 3 with TPPO detritus is stirred with 500 ml of water/methanol (1:1 parts by volume, 455 g) for 5 min; the stirrer is switched off. The TPPO is now completely dissolved, clear phases! Phase separation takes place after 5 min. Lower phase 4 (LP4, 557 g, cloudy phase). The upper phase 4 is stirred again with 500 ml of water/methanol (1:1 parts by volume, 455 g) for 5 min; the stirrer is switched off. Virtually clear phases are observed! Phase separation takes place after 5 min. Lower phase 5 (LP5, 454 g, slightly cloudy phase). The upper phase 5 is washed again with 500 ml of water, the phases are separated. Lower phase 6 (LP6, 509 g, clear phase) is discarded. The upper phase 6 (303 g) is concentrated on a rotary evaporator (45° C. bath, full oil-pump vacuum).

This gives 60.4 g of product of value (yellow oil). The desired product was able to be isolated with ca. 97.2 A % purity (E&Z) and about 93% yield, based on geranyl acetone; based on C3-phosphonium salt, the yield is 84.0%.

HPLC Method 2

RT Substance Area % 6.14 TPPO 1.51 10.79 E-Geranyl acetone 0.24 20.64 Z-C16-cyclopropane 6.03 22.25 E-C16-cyclopropane 91.21

Example 2 Wittig Reaction Starting from the TPP-Bromopropane Salt with NaH

Feed Materials:

250 ml (3082.3 mmol) I Tetrahydrofuran 12.3 eq 222.25 g M = 72.11 g/mol 126.6 g (250 mmol) II C₄ salt HPLC - 91.67%   1 eq by weight 22 g (550 mmol) III Sodium hydride in mineral  2.2 eq oil 60% strength M = 24 g/mol 48.6 g 240.1 mmol IV Geranyl acetone 0.96 eq 90%(E) and 6%(Z) based on (E) M = 194.32 g/mol  0.9 eq and (Z) 225 mmol based on (E)

The C₄ salt (II) is introduced as initial charge at room temperature in THF (I). The sodium hydride (III) is washed 3× with in each case 100 ml of n-hexane, dried in the nitrogen stream and added. The white suspension is then stirred for 4.5 h at room temperature (conversion check via HPLC). Geranyl acetone (IV) is then added and the mixture is heated at 35° C. for 21 h. 500 ml of n-heptane are then added to the yellowish suspension. THF is then removed on a rotary evaporator. The remaining suspension is admixed with 500 ml of water/methanol and the phases are separated. The aqueous phase is extracted 2× with 250 l of n-heptane. The combined organic phases are washed 6× with 250 ml water/methanol in order to separate off formed NaBr and TPPO. The organic phase is dried over sodium sulfate and concentrated on a rotary evaporator at 50° C./10 mbar. This gives 50.6 g of product of value in the form of a brown, clear oil.

Yield (%) Yield (%) Yield (%) based based on based on on E-C₁₆- Geranyl 100% Σ E&Z Σ E&Z cyclopropane acetone Yield area % area % area % [mmol] [g] [g] [%] [g] [%] [g] [%] 240 52.4 49.3 94.2 49.2 93.9 225 49.1 46.1 94.0

HPLC Method 2:

Sample: 36257/ A RT Substance Area % 2.68 C₃ salt 3.27 C₄ salt 6.05 TPPO 10.65 E-Geranyl acetone 0.4 20.57 Z-C₁₆-cyclopropane 6.0 22.16 E-C₁₆-cyclopropane 91.2

HPLC Method 1:

Sample: 36257/ A % by RT Substance Area % weight 1.05 C₃ salt 1.10 C₄ salt 1.27 TPPO 3.64 Geranyl acetone 14.53 C₁₆-cyclopropane 97.2 97.5

Example 3 Ring Opening with BF₃ Etherate and Glacial Acetic Acid

Feed Materials:

Molecular Quantitative Weight Amount Substance Purity % g/mol Mass g Mol Eq C₁₆- 90.3 (based 218.38 109.2 0.452 1 cyclopropane on E & Z) Glacial acetic 100 60.05 1914 31.875 70.5 acid BF₃ etherate 100 141.93 9.05 0.0638 0.14 Glacial acetic 100 60.05 204 3.4 7.5 acid

The C₁₆-cyclopropane (I) is dissolved in glacial acetic acid (II) and produces a clear, yellow solution. The BF₃ etherate is prediluted in glacial acetic acid and added over the course of 2 min at RT. The solution slowly becomes darker, no heat tonality. Stirring is carried out overnight at RT. A dark brown, clear solution (HPLC analysis) is obtained. After 27 h at RT, 2.5 l of water and 1 l of cyclohexane are added to the clear, dark brown solution, and the phases are separated. The aqueous phase is extracted twice with 0.5 l cyclohexane. The combined organic phases are washed in succession with 4×0.2 l of water, 0.25 l of saturated NaHCO₃ solution and again 0.25 l of water. The organic upper phase is dried over sodium sulfate and concentrated on a rotary evaporator at 40° C./4 mbar. This gives 122.5 g of product of value in the form of an orange liquid crude product (theory 118.3 g) (HPLC analysis method 2: A). The homofarnesyl acetate is obtained in a 3Z,7E:3E,7E ratio of 1:2.45.

In the case of the first aqueous phase, a further ca. 150 ml of organic phase separated out overnight. This was isolated and likewise washed several times with water and saturated NaHCO₃. The organic upper phase was dried over sodium sulfate and concentrated on a rotary evaporator at 40° C./4 mbar. This gives a further 7.0 g of product of value (HPLC analysis method 2: B).

HPLC Method 2: Area % min 14.10 15.18 16.61 17.78 18.84 20.13 20.68 22.27 10.70 12-Acetoxy- 3E/Z, 3Z,7E- 3E,7E- Z-C16- E-C16- Geranyl Hofa acetate 7Z-Hofa Hofa Hofa cyclo- Cyclo- acetone stereoisomers acetate acetate acetate propane propane >28 Starting 5.1 0 0 0 0 0 0 5.7 84.6 0.1 material A 3.6 3.4 7.1 2.8 6.8 17.2 42.1 0 0.2 7.9 B 3.0 2.6 6.6 2.1 6.9 16.1 40.5 0 0.3 8.3

The desired product was able to be isolated with ca. 60% purity and about 62% yield. A post-extraction of the first aqueous phase was able to increase the yield to 65%.

Example 4 Ring Opening with AlCl₃ and Glacial Acetic Acid

Feed Materials:

Molecular Quantitative Weight amount Substance Purity % g/mol Mass g mol Eq C₁₆- 94.6 (based 218.38 34.5 0.15 1 cyclopropane on E & Z) 88.7 (based on E) Glacial acetic 100 60.05 192.4 3.2 21 acid Aluminum 100 133.34 7.27 0.055 0.36 trichloride

The C₁₆-cyclopropane is introduced as initial charge in glacial acetic acid at room temperature. Aluminum trichloride is added. Stirring is carried out for 17.5 h at room temperature (conversion check via thin-layer chromatography and HPLC). The reaction mixture is then admixed with 600 ml of water and extracted 2× with 200 ml of cyclohexane. The organic phases are combined (pH=3-4) and washed with 120 g of NaOH (5% strength). The organic phase is dried over sodium sulfate and concentrated on a rotary evaporator at 50° C./10 mbar. This gives 35.4 g of product of value in the form of an orange liquid, i.e. at a purity of 96.4 HPLC area % in a yield of 90% based on the sum of the isomers.

HPLC Method 2:

Sample: A Ratio RT Substance Area % E/Z 10.65 E-Geranyl acetone 0.4 20.35 3Z,7Z-homofarnesyl chloride 1.8 1 20.69 C₁₆-cyclopropane Z 21.29 3Z,7E-homofarnesyl chloride 4.4 2.4 22.27 C₁₆-cyclopropane E (identical to 3E,7Z-homofarnesyl chloride) 22.27 3E,7Z-homofarnesyl chloride 24.1 1 23.79 3E,7E-homofarnesyl chloride 66.1 2.7 Σ 96.4 Area %

Example 5 Substitution of the Homofarnesyl Chloride to Give Homofarnesol

Feed Materials:

Molecular Quantitative weight Mass/ amount Substance Purity [%] [g/mol] volume [mol] Eq Homofarnesyl 96.3 254.842 12.6 g 0.0475 1 chloride (based on all homofarnesyl chloride isomers) 1:2.7 3E,7Z:3E,7E 1:2.4 3Z,7Z:3Z,7E Toluene   10 mL Sodium formate 97 68.01 19.4 g 0.285 6 Tetrabutyl- 322.38 2.28 g 0.0071 0.15 ammonium bromide NaOH 25 40  7.6 g 0.0475 1

Homofarnesyl chloride is introduced as initial charge in toluene at room temperature. Sodium formate and tetrabutylammonium bromide are added. The suspension is brought to 110° C. and stirred for 10 h (conversion check via HPLC; sample preparation: 1 ml of reaction mixture is stirred with 1 ml of NaOH 25% strength for 1 h at room temperature. Toluene phase→HPLC). The reaction mixture is then admixed with 25% strength NaOH and stirred for 60 min at room temperature (ph=10-11). The present suspension is then added to 300 ml of dist. water and extracted with 100 ml of toluene. The organic phase is washed 1× with 150 ml, 1× with 100 ml demineralized water, dried over sodium sulfate and evaporated to dryness on a rotary evaporator at 50° C./10 mbar. This gives 11.1 g of product of value in the form of a brown, clear oil, i.e. at a purity of 71.4 HPLC area % in a yield of 70%, based on the sum of the isomers 3E,7E- and 3E,7Z-homofarnesol.

HPLC Method 2:

Sample: Ratio RT Substance Area % E/Z 13.59 3E,7Z-homofarnesol 17.6 1 14.79 3E,7E-homofarnesol 53.8 3.1

Example 6 Chemical Cyclization of Homofarnesol to Give Ambrox

Various process variants for a chemical cyclization are described below:

a) Conditions: 2-Nitropropane, Conc. Sulfuric Acid, −78° C.

Feed Materials:

Molecular Quantitative weight Mass/ amount Substance Purity % g/mol volume mol Eq Homofarnesol 90.1 236.4 1 g 0.00423 1 (3Z,7E: 5% and 3E,7E: 85.1% chiral HPLC) Conc. sulfuric 98.08 3.9 g/ 0.04 9.4 acid 2.12 mL 2-Nitropropane 89.09 99.2 g/ 100 mL

Conc. sulfuric acid was introduced as initial charge in 50 ml of 2-nitropropane under a nitrogen atmosphere at −78° C. A solution of 1 g of homofarnesol in 50 ml of 2-nitropropane was added dropwise at −78° C. over the course of 30 min. Reaction control was carried out via TLC: after 2 h, the starting material was used up. For the work-up, the reaction mixture was brought to 0° C. and then slowly added to 200 ml of saturated NaHCO₃ solution. Extraction was carried out three times with 100 ml of diethyl ether. The organic phases were combined and washed with 100 ml of saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness on a rotary evaporator. An isomer mixture of at least (−) and (+)-ambrox and 9b-epi-(−)-ambrox and 3a-epi-(−)-ambrox (see above) was obtained.

b) Conditions: 2-Nitropropane, Trifluoromethanesulfonic Acid, −78° C. Feed Materials:

Molecular Quantitative weight Mass/ amount Substance Purity % g/mol volume mol Eq Homofarnesol 90.1 236.4 1 g 0.00423 1 (3Z,7E: 5% and 3E,7E: 85.1% chiral HPLC) Trifluoromethane- 150.08 6 g/3.54 ml 0.04 9.4 sulfonic acid 2-Nitropropane 89.09 99.2 g/ 100 ml

Trifluoromethanesulfonic acid was introduced as initial charge in 50 ml of 2-nitropropane under a nitrogen atmosphere at −78° C. A solution of 1 g of homofarnesol in 50 ml of 2-nitropropane was added dropwise at −78° C. over the course of 30 min. The reaction control was carried out via TLC: after 2 h, the starting material was used up. For the work-up, the reaction mixture was brought to 0° C. and then slowly added to 200 ml of saturated NaHCO₃ solution. Extraction was carried out 3 times with 100 ml of diethyl ether. The organic phases were combined and washed with 100 ml of saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness on a rotary evaporator. An isomer mixture of at least (−) and (+)-ambrox and 9b-epi-(−)-ambrox and 3a-epi-(−)-ambrox (see above) was obtained.

c) Conditions: 2-Nitropropane, Fluorosulfonic Acid, −78° C.

(see P. F. Vlad et al. Khimiya Geterotsiklicheskikh Soedinenii, Engl. Transl. 1991, 746)

Feed Materials:

Molecular Quantitative weight Mass/ amount Substance Purity % g/mol volume mol Eq Homofarnesol 83.3 236.4 1 g 0.00423 1 (3Z,7E: 3E,7E = 1:15,1) Fluorosulfonic 100.07 4 g 0.04 9.4 acid 2-Nitropropane 89.09 99.2 g/ 100 ml

Fluorosulfonic acid was introduced as initial charge in 50 ml of 2-nitropropane under a nitrogen atmosphere at −90° C. A solution of 1 g of homofarnesol in 50 ml of 2-nitropropane was added dropwise at −90° C. Stirring was carried out for a further 25 h at −78° C. For the work-up, the reaction mixture was brought to 0-5° C. and then slowly added to 200 ml of saturated NaHCO₃ solution. Extraction was carried out 3 times with 100 ml of diethyl ether. The organic phases were combined and washed with 100 ml of saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness on a rotary evaporator. An isomer mixture of at least (−) and (+)-ambrox and 9b-epi-(−)-ambrox and 3a-epi-(−)-ambrox (see above) was obtained and separated via kugelrohr distillation.

Reference is made expressly to the disclosure of the documents mentioned herein. 

1-12. (canceled)
 13. A process for preparing compounds of the general formula I

in which R₁ is a straight-chain or branched, optionally mono- or polyunsaturated hydrocarbyl radical, and R₂ is H or C₁-C₆-alkyl, which comprises a) reacting a carbonyl compound of the formula II

in which R₁ and R₂ have the meanings given above, by means of Wittig olefination to give a cyclopropane of the general formula (III)

in which R₁ and R₂ have the meanings given above, b) reacting the cyclopropane of the formula III with ring opening, to give a compound of the formula IV

in which R₁ and R₂ have the meanings given above, and X is halogen or O—R′, in which R′ is H, acyl, Tf-acetyl or SC₂—R″, in which R″ is alkyl or aryl; and c) converting the compound of the general formula IV to the compound of the general formula I.
 14. The process according to claim 13, wherein a cyclopropylphosphonium salt is used for the Wittig olefination according to stage a).
 15. The process according to claim 14, wherein the cyclopropylphosphonium salt is a triphenylphosphonium compound of the formula V

in which Z⁻ is the anion of a strong acid.
 16. The process according to claim 15, wherein Z⁻ is a halide.
 17. The process according to claim 15, wherein Z⁻ is bromide.
 18. The process according to claim 15, wherein the compound of the formula V is prepared by reacting a) bromobutyrolactone with triphenylphosphine and then thermally decarboxylating the reaction product, or b) reacting 1,3-dibromopropane with triphenylphosphine and then cyclizing the reaction product.
 19. The process according to claim 13, in which the ring-opening in stage b) takes place in the presence of a Lewis acid or Brönstedt acid/protonic acid and a nucleophile.
 20. The process according to claim 17, wherein the ring opening takes place essentially stereoselectively, in particular E-selectively (with respect to R₁).
 21. The process according to claim 13, wherein, in stage c), the compound of the general formula IV is converted to a compound of the general formula I by, when X is OR′, carrying out an ester cleavage, or when X is halogen, converting the halide to an ester and then cleaving this ester.
 22. The process according to claim 13, wherein, in stage c), the compound of the general formula IV is converted to a compound of the general formula I by, when X is OR′, carrying out an ester cleavage, or when X is halogen, converting the halide to a formate ester, and then cleaving this ester.
 23. The process according to claim 13, in which a product comprising a (3E,7E)-homofarnesol of the formula Ia

is obtained.
 24. The process according to claim 20, where, in stage a), E-geranyl acetone of the formula IIa

is reacted with cyclopropylphosphonium halogenide, so that the cyclopropane of the formula IIIa

is obtained.
 25. A compound of the formula III


26. A compound of the formula IIIa


27. A process for preparing enantiomerically pure ambrox or a stereoisomer mixture of ambrox, where (3E,7E)-homofarnesol is prepared by the process according to claim 13 and the homofarnesol formed in this way is reacted chemically or enzymatically to give enantiomerically pure ambrox or a stereoisomer mixture of ambrox. 